Morin post-treatment surpassed calpeptin in ameliorating 3-NP-induced cortical neurotoxicity via modulation of glutamate/calpain axis, Kidins220, and BDNF/TrkB/AKT/CREB trajectory
MH and/or CP mitigate HD via deactivating glutamate/calpain, KIDINS220, neuro-inflammation, and oxidative stress, while activating the BDNF/TrkB/AKT/CREB survival pathway. BDNF: brain-derived neurotrophic factor: CP: calpeptin: CREB: cAMP response element-binding protein: KIDINS220: Kinase D interac...
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Published in | International immunopharmacology Vol. 116; p. 109771 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
Elsevier B.V
01.03.2023
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Subjects | |
Online Access | Get full text |
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Summary: | MH and/or CP mitigate HD via deactivating glutamate/calpain, KIDINS220, neuro-inflammation, and oxidative stress, while activating the BDNF/TrkB/AKT/CREB survival pathway. BDNF: brain-derived neurotrophic factor: CP: calpeptin: CREB: cAMP response element-binding protein: KIDINS220: Kinase D interacting substrate of 220 kDa/Ankyrin repeat-rich membrane spanning; interleukin-1 beta: MDA: malondialdehyde: MH: morin hydrate: NF-κB: nuclear factor kappa B: TNF-α: tumor necrosis factor-alpha TrkB: Tropomyosin receptor kinase B.
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•HD causes memory/cognition and motor dysfunction.•MH, to a lesser extent CP conferred neuroprotection against HD motor/memory deficits.•MH, CP inhibited the cortical glutamate/calpain axis & Kidins220.•MH, CP activated BDNF/TrkB/AKT/CREB trajectory.•MH, CP abated NF-κB, TNF-α, IL-1β, & lipid peroxidation.•Their combination showed additive effects on inflammatory/oxidative markers.
The neuroprotective capacity of morin hydrate (MH), a potent antioxidant flavonoid, and calpeptin (CP), a calpain inhibitor, was documented against different insults but not Huntington’s disease (HD). Accordingly, we aim to assess the neuroprotective potential of MH and/or CP in a 3-nitropropionic acid (3-NP)-induced HD model. The 3-NP-treated rats were post-treated with saline, MH, CP, or MH + CP for a week. Post-treatment with MH and/or CP amended motor function (beam walking test) and short-/ long-term spatial memory (novel object recognition test) and improved cortical microscopic architecture. On the molecular level, MH, and to a lesser extent CP, inhibited the cortical content/expression of glutamate, calpain, and Kidins220 and abated the inflammatory molecules, nuclear factor (NF)-κB, tumor necrosis factor-α, and interleukin-1β, as well as lipid peroxidation. However, MH, but barely CP, activated the molecules of the neuroprotective trajectory; viz., brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase receptor B (TrkB), protein kinase B (AKT), and cAMP response element-binding protein (CREB). Compared to the single treatments, the combination regimen mediated further reductions in the cortical contents of glutamate, calpain, and Kidins220, effects that extended to entail the anti-inflammatory/anti-oxidant potentials of MH and to a greater extent CP. However, the combination of MH strengthened the fair effect of CP on the survival signaling pathway BDNF/TrkB/AKT/CREB. In conclusion, MH, CP, and especially their combination, afforded neuroprotection against HD through curbing the glutamate/calpain axis, Kidins220, as well as NF-κB-mediated neuroinflammation/oxidative stress, besides activating the BDNF/TrkB/AKT/CREB hub that was partly dependent on calpain inhibition. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1567-5769 1878-1705 |
DOI: | 10.1016/j.intimp.2023.109771 |